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J Org Chem. 2016 Jul 1;81(13):5547-65. doi: 10.1021/acs.joc.6b00889. Epub 2016 Jun 21.

Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions.

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Department of Chemistry, University of Warwick , Coventry, West Midlands CV4 7AL, U.K.
Department of Chemistry, University of Pittsburgh , Pittsburgh Pennsylvania 15260, United States.
Dipartmento di Scienze Chimiche e Geologiche, Univerita degli Studi di Modena e Reggio Emilia , Via Campi 103, 41125 Modena, Italy.


The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG(⧧) rotation varied between <8.0 and 31.0 kcal mol(-1)). The most important factor in controlling the rate of rotation was the level of alkene substitution, followed by the size of the nitrogen substituent and, finally, the size of the acyl substituent. Tertiary enamides with four alkenyl substituents exhibited half-lives for rotation between 5.5 days and 99 years at 298 K, sufficient to isolate enantiomerically enriched atropisomers. The radical cyclizations of a subset of N-alkenyl-N-benzyl-α-haloacetamides exhibiting relatively high barriers to rotation round the N-alkenyl bond (ΔG(⧧) rotation >20 kcal mol(-1)) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol(-1)) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical-polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature.

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